Alzheimer's disease is the most common neurodegenerative disorder and is characterized clinically by cognitive dysfunction. Classic neuropathological features of the disease include the formation of extracellular amyloid plaques, intraneuronal deposition of abnormally phosphorylated and aggregated tau protein into neurofibrillary tangles, and gliosis. Glial pathology has generally been considered a secondary, or reactive, change. However, recent advances in understanding normal and pathological glial biology have instead suggested that glia may play an active role in neurological disorders, including Alzheimer's disease. Here we take a genetic approach to define proteins and pathways mediating the influence of glia on Alzheimer's-associated neurodegeneration. Taking advantage of the advanced molecular and genetic tools, short lifespan, and conserved glial biology in Drosophila we will identify glial proteins and pathways that can influence tau neurotoxicity in aging adult brains. In proof of principle studies we validate a novel system for studying non-cell autonomous neurodegeneration in tauopathy. In addition, based on the observation that many genes implicated in Alzheimer's disease through genome wide genetic association studies are expressed predominantly or substantially in glial cells, we will test the effect of upregulating and downregulating these genes in fly glia on tau-induced neurotoxicity. These studies will develop a novel methodology for studying the effect of glia on the neurodegeneration associated with Alzheimer's disease and will ultimately expand the array of molecular and cellular targets relevant for therapy development in this common and devastating disorder.